Influence of syngeneic peritoneal macrophages (MPhi) on NK reactivity of mice and metastasis formation in the lungs was studied. Thioglycollate-elicited macrophages (TG-MPhi) inoculated i.v. caused the inhibition of the ability of mice to eliminate tumor cells from the lungs and a dramatic augmentation of metastasis formation. In parallel, inoculated TG-MPhi suppressed the cytotoxic activity of spleen cells of the recipients and abrogated the stimulatory effects of poly I:C on NK activity as well as on resistance to metastasis. These effects were mediated only by TG-MPhi but not resident MPhi or MPhi elicited by proteosepeptone or C. parvum. Adoptively transferred, activated tumoricidal TG-MPhi had no antimetastatic effect and were able to augment metastasis formation as well as nontumoricidal TG-MPhi. Both viable and disrupted TG-MPhi induced neutrophil aggregation in the capillary beds of the lungs and probably released some substances with anaphylactic activity which may influence the NK reactivity of mice and permeability of the vessels for tumor cells. The involvement of NK cells in the antimetastatic effect of anticoagulant drugs was also investigated. Heparin had substantial inhibitory effects on the formation of metastases by B16 melanoma cells. However, in mice with NK activity depressed by pretreatment with anti-asialo GM1, the antimetastatic effect of heparin was completely abrogated. In contrast, stimulation of NK cell activity by poly I:C resulted in augmentation of the antimetastatic effect of heparin. These data provide better understanding of some of the factors influencing the metastatic process and particularly add further evidence for the important role of NK cells in the control of the metastatic spread of tumors in mice.